EP0755928B1 - Derives 5-aminoflavone - Google Patents

Derives 5-aminoflavone Download PDF

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Publication number
EP0755928B1
EP0755928B1 EP96901492A EP96901492A EP0755928B1 EP 0755928 B1 EP0755928 B1 EP 0755928B1 EP 96901492 A EP96901492 A EP 96901492A EP 96901492 A EP96901492 A EP 96901492A EP 0755928 B1 EP0755928 B1 EP 0755928B1
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Prior art keywords
compound
alkyl
mixture
mmol
brs
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EP96901492A
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German (de)
English (en)
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EP0755928A4 (fr
EP0755928A1 (fr
Inventor
Tsutomu Akama
Shun-Ichi Ikeda
Hiroyuki Oakwood Apartments D205 ISHIDA
Uichiro Kimura
Katsushige Gomi
Hiromitsu Saito
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KH Neochem Co Ltd
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Kyowa Hakko Kogyo Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones

Definitions

  • the present invention relates to novel 5-aminoflavone derivatives possessing anti-bacterial activity, anti-estrogenic activity, and antitumor activity.
  • 5-Aminoflavone derivatives having anti-bacterial, anti-estrogenic and/or anti-tumor activity as well as their preparation have been disclosed in EP-0 638 566 A1.
  • the present invention provides a 5-aminoflavone derivative represented by the formula (I) : wherein X represents (i) C 1 -C 6 alkyl substituted with 1 to 3 substituents selected from a group consisting of NR 3 R 4 ⁇ wherein R 3 and R 4 are the same or different and represent hydrogen, C 1 -C 6 alkyl which may be substituted with NR 5 R 6 (wherein R 5 and R 6 are the same or different and represent hydrogen, or C 1 -C 6 alkyl), or R 3 and R 4 are taken together to form a heterocyclic group containing the sandwiched nitrogen atom in the ring which may be substituted with 1 to 3 substituents selected from a group consisting of C 1 -C 6 alkyl and NR 7 R 8 (wherein R 7 and R 8 are the same or different and represent hydrogen, or C 1 -C 6 alkyl) ⁇ , halogen, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, C
  • salts of Compound (I) there are pharmaceutically acceptable acid or base addition salts, for example, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, and the like, and organic acid salts such as methanesulfonate, oxalate, acetate, mabonate, succinate, fumarate, maleate, tartrate, citrate, and the like as well as base addition salts such as sodium salt, potassium salt, and the like.
  • inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, and the like
  • organic acid salts such as methanesulfonate, oxalate, acetate, mabonate, succinate, fumarate, maleate, tartrate, citrate, and the like
  • base addition salts such as sodium salt, potassium salt, and the like.
  • Compound (Ia) which is Compound (I) wherein X is substituted lower alkyl can be prepared according to the following scheme: (wherein X a represents substituted lower alkyl in the definition of X, and Y 1 and Y 2 are the same as defined).
  • Compound (Ia) is prepared by simultaneous removing of the pivaloyl group and esterification in Compound (II), prepared by Reference Example 1 or modified method thereof, under heating in the presence of conc. sulfuric acid with the solvent of the carboxylic acid corresponding to the substituted lower alkanoyl moiety.
  • the sulfuric acid is used preferably in concentration from 1 to 18 normality.
  • the reaction is normally carried out under from room temperature to the boiling point of the corresponding solvent, preferably from 50 to 100 °C. The reaction completes in 0.1 to 10 hours.
  • Compound (Ib) which is Compound (I) wherein X is unsubstituted or substituted lower alkoxy can be prepared according to the following scheme: (wherein X b represents unsubstituted or substituted lower alkoxy in the definition of X, and Y 1 and Y 2 are the same as defined)
  • Compound (Ib) can be obtained by the reaction of (III) prepared by Reference Example 2 or modified method thereof, if necessary, in the presence of 0.1 to 1 equivalent of dimethylaminopyridine with 1 to 5 equivalents of the compound represented by (X b CO) 2 O. The reaction is carried out at 0 °C to room temperature and completes in 1 to 10 hours.
  • Compound (Ic) which is Compound (I) wherein X is NR 1 R 2 (wherein R 1 and R 2 are the same as defined) can be prepared according to the following scheme. [wherein X c represents NR 1 R 2 (wherein R 1 and R 2 are the same as defined) in the definition of X, and Y 1 and Y 2 are the same as defined].
  • Compound (Ic) can be obtained by treating Compound (Vc), prepared by step 3, in a solvent, for example, tetrahydrofurane and the like, with 1 to 10 equivalents of formic acid-triethylamine in the presence of 0.01 to 0.2 equivalent of palladium tetrakistriphenylphosphine. The reaction is carried out at 0 °C to room temperature, and completes in 1 to 10 hours.
  • a solvent for example, tetrahydrofurane and the like
  • Compound (Ia) can also be prepared according to the following reaction scheme. (wherein X a , Y 1 , and Y 2 are the same as defined)
  • Compound (Va) can be obtained by the reaction of Compound (IV) prepared by Reference Example 3 or modified method thereof, with 1 to 20 equivalents of the carboxylic acid or its activated derivative corresponding to substituted lower alkanoyl moiety in Compound (Ia) in an inert solvent in the presence of 1 to 20 equivalents of a condensation reagent or a base.
  • activated derivatives of a carboxylic acid acid halide, acid anhydride, several activated ester, and the like are used.
  • inert solvents dichloromethane, dichloroethane, toluene, dimethylformamide and the like are used.
  • condensation reagents carbonyl diimidazole, dicyclohexylcarbodiimide, 2-chloro-N-methylpyridinium iodide, and the like are used.
  • bases tertiary amine such as pyridine, triethylamine, etc., potassium carbonate, sodium carbonate, sodium hydride, and the like are used.
  • the reaction is normally carried out under from 0 °C to the boiling point of the used solvent, preferably from room temperature to 80 °C, and completes in 1 hour to 1 week.
  • Compound (Ia) can be obtained by treating Compound (Va) prepared by step 5 according to a modified method of the method of step 4 above.
  • the resulting Compound (Ia) can partly be used as the synthetic intermediate to be converted to further novel derivatives.
  • Compound (Iaa), wherein X a is (CH 2 ) n NR 3 R 4 (wherein n is an integer of 1 to 6, and R 3 and R 4 are the same as defined) in Compound (Ia) can be obtained by the reaction of Compound (Iab), wherein X a is (CH 2 ) n Y (Y represents chlorine, bromine, and iodine) with 1 to 10 equivalents of HNR 3 R 4 (wherein R 3 and R 4 are the same as defined above) in a inert solvent, if necessary, in the presence of base.
  • inert solvents dimethylformamide, dimethylsulfoxide, tetrahydrofuran, dioxane, and the like are used.
  • triethylamine, diisopropylethylamine, pyridine, dimethylaminopyridine, potassium carbonate, sodium carbonate, and the like are used as bases.
  • the reaction is carried out under from 0 to 100 °C, preferably from 50 to 70 °C, and completes in 1 to 10 hours.
  • Intermediates and desired compounds in the above processes can be isolated and purified by purifying methods normally used in organic synthetic chemistry, for example, filtration, extraction, washing, drying, concentration, recrystallization, and various chromatographies and the like.
  • intermediates may also be subjected to the subsequent step without purification.
  • a salt compound When a salt form of the product is desired, a salt compound can be subjected to known purification or isolation processes to give a salt form.
  • a salt for Compound (I) When a product is synthesized in free form, a salt for Compound (I) can be separated or purified after formation of salt by normal method, for example, dissolving or suspending it in an appropriate organic solvent and adding an appropriate acid or base.
  • Compound (I) and a salt thereof can also be present in the form of addition products to water or various solvents. Such addition products are also included within the scope of the present invention.
  • Compound (I) has the anti-estrogenic activity, which can be demonstrated by the decrease in uterus weight of a mature mouse.
  • Compound (I) inhibits the growth of human mammary cancer cells in the medium of a microplate and inhibits the growth of human mammary cancers transplanted into nude mice.
  • the compound possessing such the bioactivity is useful for treatment of the symptoms for which tamoxifen is useful, for example, breast cancer, non-ovulatory sterility, and paramenia.
  • Each 0.1 ml of MCF-7 cells which had been prepared in a concentration of 5 x 10 4 /ml using a medium prepared by adding 10% bovine fetal serum, 10 -8 M estradiol (manufactured by Sigma), 100 units/ml penicillin and 100 ⁇ g/ml streptomycin to RPMI1640 medium (referred to as Medium B hereinafter) was distributed in each well of 96 well-microtiter plate. The plate was allowed to stand at 37 °C for 20 hours in a CO 2 gas incubator, each 0.05 ml of samples (test compound) which had been appropriately diluted with Medium B was added thereto and the mixture was allowed to stand at 37 °C for 72 hours in a CO 2 gas incubator.
  • the tumor fragment (2 mm x 2 mm x 2mm) of human hormone dependent mammary cancer MCF-7 was transplanted subcutaneously in the flank of female BALB/c-nu/nu mouse (Nihon Crea), 7 to 9 weeks age.
  • 12.5 ⁇ g of estradiol propionate was intramuscularly administered in the femoral region two times in total, i.e., on the date of transplantation and two weeks after transplantation.
  • Mice having the tumor volume 25 to 200 mm 3 were selected 3 to 4 weeks after transplantation, and the test compounds were orally administered repeatedly to the groups (5 animals per group) for 5 days per a week, for total two weeks.
  • T/C value was obtained as the ratio of V/V 0 value of treated group relative to that of control group.
  • Table 4 Compound dose (mg/kg) T/C judgement date (day) 6 25 0.012 15, 17 7 25 0.041 18 8 25 0.15 14 9 25 0.042 14 10 25 0.070 14 11 25 0.044 18 12 25 0.035 18 13 25 0.022 24 14 25 0.013 25
  • Antibacterial activity of Compound (I) against Bacillus subtilis #10107 [Minimum Inhibition Concentration (MIC; ⁇ g/ml)] is shown in Table 5. Minimum Inhibition Concentration was determined by agar dilution method at pH 7.0. Compound MIC ( ⁇ M) 3 83.3 6 26.0 7 104 8 104
  • 2,4-Difluorophenol (104 g, 796 mmol) was dissolved in dichloromethane (800 mL). Triethylamine (132 mL) and ethyl chloroformate (92.0 mL) were added to the mixture under ice-cooling and the mixture was stirred at -10 to 0 °C for 2 hours. The reaction mixture was washed with brine and dried over anhydrous magnessium sulfate. The solvent was distilled off under reduced pressure to give 1-ethoxycarbonyloxy-2,4-difluorobenzene (156 g, yield: 97%).
  • the present invention can provide 5-aminoflavone derivatives possessing antibacterial activity, anti-estrogenic activity, and antitumor activity.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Claims (3)

  1. Dérivé de 5-aminoflavone, représenté par la formule (1) :
    Figure 00420001
    dans laquelle X représente :
    (i) un groupe alkyle en C1-6, portant de 1 à 3 substituants, choisis dans l'ensemble que forment les groupes de formule NR3R4 {où R3 et R4 peuvent être identiques ou différents et représentent chacun un atome d'hydrogène ou un groupe alkyle en C1-6, lequel peut porter un substituant de formule NR5R6 (où R5 et R6 peuvent être identiques ou différents et représentent chacun un atome d'hydrogène ou un groupe alkyle en C1-6), ou encore R3 et R4 constituent ensemble, avec l'atome d'azote qui les relie, un groupe hétérocyclique qui peut porter de 1 à 3 substituants choisis dans l'ensemble que forment les groupes alkyle en C1-6 et les groupes de formule NR7R8 (où R7 et R8 peuvent être identiques ou différents et représentent chacun un atome d'hydrogène ou un groupe alkyle en C1-6)}, les atomes d'halogène et les groupes hydroxy, alcoxy en C1-6, (alcoxy en C1-6)carbonyle, alcanoyle en C1-6, alcanoyloxy en C1-6 et vinyle,
    (ii) un groupe alcoxy en C1-6, qui peut porter de 1 à 3 substituants choisis dans l'ensemble que forment les groupes de formule NR3R4 {où R3 et R4 peuvent être identiques ou différents et représentent chacun un atome d'hydrogène ou un groupe alkyle en C1-6, lequel peut porter un substituant de formule NR5R6 (où R5 et R6 peuvent être identiques ou différents et représentent chacun un atome d'hydrogène ou un groupe alkyle en C1-6), ou encore R3 et R4 constituent ensemble, avec l'atome d'azote qui les relie, un groupe hétérocyclique qui peut porter de 1 à 3 substituants choisis dans l'ensemble que forment les groupes alkyle en C1-6 et les groupes de formule NR7R8 (où R7 et R8 peuvent être identiques ou différents et représentent chacun un atome d'hydrogène ou un groupe alkyle en C1-6)}, les atomes d'halogène et les groupes hydroxy, alcoxy en C1-6, (alcoxy en C1-6)carbonyle, alcanoyle en C1-6, alcanoyloxy en C1-6 et vinyle, ou
    (iii) un groupe de formule NR1R2 < dans laquelle R1 et R2 peuvent être identiques ou différents et représentent chacun un atome d'hydrogène ou un groupe alkyle en C1-6 qui peut porter de 1 à 3 substituants choisis dans l'ensemble que forment les groupes de formule NR3R4 {où R3 et R4 peuvent être identiques ou différents et représentent chacun un atome d'hydrogène ou un groupe alkyle en C1-6, lequel peut porter un substituant de formule NR5R6 (où R5 et R6 peuvent être identiques ou différents et représentent chacun un atome d'hydrogène ou un groupe alkyle en C1-6), ou encore R3 et R4 constituent ensemble, avec l'atome d'azote qui les relie, un groupe hétérocyclique qui peut porter de 1 à 3 substituants choisis dans l'ensemble que forment les groupes alkyle en C1-6 et les groupes de formule NR7R8 (où R7 et R8 peuvent être identiques ou différents et représentent chacun un atome d'hydrogène ou un groupe alkyle en C1-6)}, les atomes d'halogène et les groupes hydroxy, alcoxy en C1-6, (alcoxy en C1-6)carbonyle, alcanoyle en C1-6, alcanoyloxy en C1-6 et vinyle, ou encore R1 et R2 constituent ensemble, avec l'atome d'azote qui les relie, un groupe hétérocyclique qui peut porter de 1 à 3 substituants choisis dans l'ensemble que forment les groupes alkyle en C1-6 et les groupes de formule NR7R8 (où R7 et R8 peuvent être identiques ou différents et représentent chacun un atome d'hydrogène ou un groupe alkyle en C1-6) >,
    et Y1 et Y2 peuvent être identiques ou différents et représentent chacun un atome d'hydrogène ou d'halogène ou un groupe alkyle en C1-6,
    ou sel d'un tel dérivé, admissible en pharmacie.
  2. Dérivé de 5-aminoflavone, conforme à la revendication 1, dans lequel X représente un groupe alkyle en C1-6 portant de 1 à 3 substituants choisis dans l'ensemble que forment les groupes de formule NR3R4 {où R3 et R4 peuvent être identiques ou différents et représentent chacun un atome d'hydrogène ou un groupe alkyle en C1-6, lequel peut porter un substituant de formule NR5R6 (où R5 et R6 peuvent être identiques ou différents et représentent chacun un atome d'hydrogène ou un groupe alkyle en C1-6), ou encore R3 et R4 constituent ensemble, avec l'atome d'azote qui les relie, un groupe hétérocyclique qui peut porter de 1 à 3 substituants choisis dans l'ensemble que forment les groupes alkyle en C1-6 et les groupes de formule NR7R8 (où R7 et R8 peuvent être identiques ou différents et représentent chacun un atome d'hydrogène ou un groupe alkyle en C1-6)}, les atomes d'halogène et les groupes hydroxy, alcoxy en C1-6, (alcoxy en C1-6)carbonyle, alcanoyle en C1-6, alcanoyloxy en C1-6 et vinyle, ou sel d'un tel dérivé, admissible en pharmacie.
  3. Dérivé de 5-aminoflavone, conforme à la revendication 1 ou 2, dans lequel au moins l'un des symboles Y1 et Y2 représente un atome d'halogène, ou sel d'un tel dérivé, admissible en pharmacie.
EP96901492A 1995-02-06 1996-01-31 Derives 5-aminoflavone Expired - Lifetime EP0755928B1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP1774195 1995-02-06
JP17741/95 1995-02-06
JP1774195 1995-02-06
PCT/JP1996/000181 WO1996024592A1 (fr) 1995-02-06 1996-01-31 Derives 5-aminoflavone

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EP0755928A1 EP0755928A1 (fr) 1997-01-29
EP0755928A4 EP0755928A4 (fr) 1997-05-28
EP0755928B1 true EP0755928B1 (fr) 2002-04-10

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EP (1) EP0755928B1 (fr)
AU (1) AU4547496A (fr)
CA (1) CA2187197A1 (fr)
DE (1) DE69620514T2 (fr)
WO (1) WO1996024592A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6812246B2 (en) 2000-04-06 2004-11-02 The United States Of America As Represented By The Department Of Health And Human Services Aminoflavone compounds, compositions, and methods of use thereof
ATE476178T1 (de) * 2001-09-06 2010-08-15 Synorx Inc Hemmung der t-lymphozyten-aktivierung durch 3- deoxyflavonoide und relevante therapien
WO2014018741A1 (fr) 2012-07-27 2014-01-30 Emory University Dérivés hétérocycliques de flavone, compositions et procédés s'y rapportant
JP6090514B1 (ja) * 2016-05-18 2017-03-08 日本ゼオン株式会社 重合性化合物の製造方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02138277A (ja) * 1988-08-22 1990-05-28 Kyowa Hakko Kogyo Co Ltd ５‐アミノフラボン誘導体
JP2859669B2 (ja) * 1988-12-19 1999-02-17 協和醗酵工業株式会社 ５―アミノフラボン誘導体
JPH05286962A (ja) * 1992-02-14 1993-11-02 Kyowa Hakko Kogyo Co Ltd ５−アミノフラボン誘導体
JP3468589B2 (ja) * 1993-08-11 2003-11-17 協和醗酵工業株式会社 ５−アミノフラボン誘導体

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Publication number Publication date
EP0755928A4 (fr) 1997-05-28
CA2187197A1 (fr) 1996-08-15
DE69620514D1 (de) 2002-05-16
EP0755928A1 (fr) 1997-01-29
DE69620514T2 (de) 2002-11-28
AU4547496A (en) 1996-08-27
WO1996024592A1 (fr) 1996-08-15

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